Clinician Update

Clinician Update
Atrial Fibrillation
Outpatient Presentation and Management
Michael D. Ezekowitz, MBChB, DPhil, FRCP; Timothy H. Aikens, BA;
Rangadham Nagarakanti, MD; Timothy Shapiro, MD
C
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for an associated condition. The patient has a normal blood
pressure (125/80 mm Hg) and a well-controlled irregular
heart rate (72 bpm) on atenolol 50 mg daily. There are no
interval ECG changes apart from the atrial fibrillation
suggestive of an acute process. On examination, he has a
short 1/6 systolic murmur at the apex without radiation. He
has no evidence of heart failure. Neurological examination
is normal. Medications include atenolol 50 mg daily,
lisinopril 5 mg daily, metformin, atorvastatin 20 mg daily,
aspirin 325 mg daily, and clopidogrel 75 mg daily.
Immediate hospitalization is not needed.
ase Presentation—A 68-year-old white man presents
to the cardiology office complaining of mild fatigue.
A new and first finding is an irregular pulse. Atrial
fibrillation is confirmed on 12-lead ECG. He has no
additional symptoms. Four months earlier, he had a drugeluting stent placed for a discrete proximal left anterior
descending artery lesion. Past history includes hypertension, hyperlipidemia, and non–insulin-dependent diabetes
mellitus.
The first step is to establish that the patient is hemodynamically stable and whether he needs inpatient evaluation
Table 1.
Study (n)
Rate Control Versus Rhythm Control Studies
Groups (n)
Primary End Point
Results
2
Rate: diltiazem⫹additional therapy if needed (125)
Symptomatic improvement
76 patients (rate) vs 70 patients (rhythm);
(palpitations, dyspnea, dizziness)
P⫽0.317
Rhythm: pharmacological (amiodarone) and, if
necessary, DC cardioversion⫹antiarrhythmic
therapy (127)
AFFIRM3 (4060)
Rate: ␤-blockers, calcium-channel blockers (verapamil
All-cause mortality
25.9 % (rate) vs 26.7% (rhythm); 95%
and diltiazem), digoxin, or combination (2027)
confidence interval, 0.99 to 1.34; P⫽0.08
Rhythm: cardioversion as necessary⫹
antiarrhythmic drug chosen by physician (2033)
Rate: digitalis, nondihydropyridine calcium-channel
RACE4 (522)
Composite cardiovascular death,
17.2% (rate) vs 22.6% (rhythm); 95%
blocker, and/or ␤-blocker (256)
hospitalization for heart
confidence interval, 0.53 to 1.01;
failure, thromboembolic complications,
P⫽0.11
Rhythm: DC cardioversion⫹sotalol, then
severe hemorrhage, pacemaker
flecainide or propafenone if needed, then
implantation, severe adverse events
amiodarone if needed (266)
5
Rate: ␤-blockers, digitalis, calcium antagonists, or
STAF (200)
Composite death, stroke/transient
10 (rate) vs 9 events (rhythm);
atrioventricular node ablation/modification (100)
ischemic event, systemic embolism,
P⫽0.99
cardiopulmonary resuscitation
Rhythm: DC cardioversion⫹class I antiarrhythmic
agents or sotalol, or if heart disease or
impaired LV function, ␤-blocker and/or amiodarone (100)
Rate: ␤-blockers, nondihydropyridine calcium
HOT CAFE6 (205)
Composite death, thromboembolic
Odds ratio,1.98; 95% confidence
blockers, digoxin, or combination (101)
complications, and intracranial
interval, 0.28 to 22.3; P⫽0.71
or other major hemorrhage
Rhythm: DC cardioversion⫹antiarrhythmic
therapy as indicated (104)
Rate: ␤-blockers, digoxin, or pacemaker and AV
AF CHF7 (1376)
Composite of cardiovascular death,
45.8% (rate) vs 42.7% (rhythm),
node ablation if necessary (694)
stroke, or worsening of heart failure
P⫽0.20
Rhythm: DC cardioversion amiodarone, then
sotalol and dofetilide if needed (682)
PIAF (252)
PIAF indicates Pharmacological Intervention in Atrial Fibrillation; DC, direct current; AFFIRM, Atrial Fibrillation Follow-up Investigation of Rhythm Management; RACE,
Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group; STAF, Strategies of Treatment of Atrial Fibrillation; HOT CAFE, How to Treat
Chronic Atrial Fibrillation; AF CHF, atrial fibrillation and congestive heart failure; and AV, atrioventricular.
From the Lankenau Institute for Medical Research, Wynnewood, PA (M.D.E., T.H.A., T.S.) and Louisiana State University School of Medicine, New
Orleans, LA (R.N.).
Correspondence to Michael D. Ezekowitz, MBChB, DPhil, FRCP, Lankenau Institute for Medical Research, 100 Lancaster Ave, Suite G36,
Wynnewood, PA 19096. E-mail [email protected]
(Circulation. 2011;124:95-99.)
© 2011 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.110.967455
95
96
Circulation
July 5, 2011
Management goals are to rule out reversible causes of atrial
fibrillation, maintain the heart rate at rest and with exercise in
the physiological range, consider conversion to sinus rhythm,
and determine which stroke prevention measures are needed.
Reversible Causes of Atrial Fibrillation
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Reversible causes of atrial fibrillation are conveniently separated into cardiac and noncardiac causes. Noncardiac causes
(electrolyte imbalance, thyrotoxicosis, fever from any cause
[particularly pneumonia], pharmacological and recreational
drug use, and alcohol use) were ruled out by history and
physical and simple blood tests (thyroid function tests, serum
electrolytes, and urine and serum toxicology).
The cardiac causes of atrial fibrillation include any mechanism resulting in structural and functional changes to the
heart. Transthoracic echocardiogram revealed moderate left
ventricular hypertrophy but normal left ventricular systolic
function, no evidence of valvular disease, normal left atrium
and no pericardial effusion. An acute ischemic event was
unlikely in view of the nonischemic ECG, no regional wall
motion abnormalities by echocardiogram, and the absence of
symptoms of ischemia.
Rate Control
Rate control, both at rest and with exercise, is central to the
management of patients with atrial fibrillation. In this case,
the patient was receiving a ␤-blocker for his coronary disease
and hypertension. His heart rate at presentation was acceptable. There is currently debate as to whether strict rate control
at rest and with exercise is preferred over a more lenient
approach. A recent report suggests that a lenient approach is
acceptable.1 Drug options for maintaining a patient’s heart
rate within the physiological range include ␤-blockers,
calcium-channel blockers such as diltiazem and verapamil,
and digoxin. ␤-Blockers are especially useful in the presence
of associated coronary artery disease or myocardial ischemia
with atrial fibrillation. Calcium-channel blockers are effective
in short-term and long-term rate control, but should be
avoided in patients with systolic heart failure because of
negative inotropic effects. Digoxin may be useful in combination with ␤-blockers in patients with heart failure. In this
case, ␤-blocker was recommended, given concomitant coronary artery disease and hypertension.
Cardioversion
The randomized trials that have compared rate control with
cardioversion have shown no mortality benefit to either
management strategy (Table 1).2–7 However, remodeling of
the left atrium, both mechanically and electrically, may be
minimized by early cardioversion to sinus rhythm.8 Other
indications for cardioversion are patient symptoms. Usually,
long-term success with cardioversion requires the concomitant use of an antiarrhythmic drug.9 For patients with symptomatic recurrent atrial fibrillation who failed 1 antiarrhythmic drug trial, curative catheter ablation should be
considered. The most common approach currently used is
exclusion of triggers by isolating pulmonary veins from the
left atrium with linear or circumferential ablation. In this
case, the patient was hemodynamically stable, and the deci-
Table 2.
Atrial Fibrillation Stroke Risk Stratification Schemes
Schema and Components
Points
AF Investigators10
Age ⱖ65 y
n/a
History of Hypertension
n/a
Previous stroke/transient ischemic
attack
n/a
Diabetes mellitus
n/a
CHADS211
Congestive heart failure
1
Hypertension
1
Age ⱖ75 y
1
Diabetes mellitus
1
Stroke/transient ischemic attack
2
Framingham
Age
0–10
Female gender
6
Systolic blood pressure
0–4
Diabetes mellitus
5
Prior ischemic stroke/transient
ischemic attack
6
7th ACCP CHA2DS2VASc12
Congestive heart failure/LV
dysfunction
1
Hypertension
1
Age ⱖ75 y
2
Diabetes mellitus
1
Stroke/transient ischemic attack
2
Vascular disease (prior myocardial
infarction, peripheral arterial
disease, or aortic plaque
1
Age 65 to 74 y
1
Female gender
1
AF indicates Atrial Fibrillation; n/a, not applicable; and LV, left ventricular.
sion to electrically cardiovert the patient was deferred (in case
of spontaneous cardioversion) but not excluded. The current
recommendation is therapeutic anticoagulation for at least 3
weeks before and at least 4 weeks after cardioversion. The
cardioversion subanalysis of the RE-LY study demonstrated
dabigatran to be a reasonable alternative to warfarin for stroke
prevention in patients requiring cardioversion.10
Stroke Prevention
The major complication of atrial fibrillation is stroke. The
central pharmacological approach to stroke prevention in
atrial fibrillation is anticoagulation. The decision to anticoagulate involves balancing stroke prevention and bleeding
risk. Risk stratification algorithms have been developed
(Table 2). The first one was developed in 1995 by the Atrial
Fibrillation Investigators.11 These led to a quantified risk
stratification system currently in use, which carries the
acronym CHADS2 (congestive heart failure, hypertension,
age ⱖ75 years, and diabetes mellitus are each assigned 1
point; previous stroke or transient ischemic attack is
Ezekowitz et al
Table 3.
AF Management
97
Novel Oral Anticoagulants
Pharmacological
Agent
Type
Dosing
Bioavailability,
absolute or
relative, %
Dabigatran
Tecafarin
Rivaroxaban
Apixaban
Edoxaban
Direct thrombin
inhibitor
Vitamin K antagonist
Factor Xa inhibitor
Factor Xa inhibitor
Factor Xa inhibitor
Fixed, twice daily
Once daily
Fixed, once daily
Fixed, twice daily
Fixed, once daily
Absolute, 6.5
NA
Relative, 60 to 80
Absolute, 60 to 66
Absolute, 50
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Half-life, h
14–17
107–140
5–13
8–15
9–11
Excretion
80% Renal
100% esterases and
hepatobiliary
Dual mechanism, 66%
renal
25% Renal
Dual mechanism, 35% renal
Drug interactions
P-glycoprotein
Low potential compared to
warfarin
CYP3A4 and
P-glycoprotein
CYP3A4
CYP3A4 and P-glycoprotein
Phase III results
RELY study17
completed. D 150
superior (1.1%;
P⬍0.001) and D 110
noninferior (1.5%;
P⫽0.34) to warfarin
(1.7%) for stroke
prevention.*
Phase 2/3 study
completed19
Greater time in therapeutic
range with tecafarin vs
warfarin (71% vs 59%)
ROCKET-AF study20
completed Rivaroxaban
20 mg and 15 mg daily
(renal patients)
noninferior (1.7%;
P⬍0.001) vs warfarin
(2.1%) for prevention of
stroke and systemic
thromboembolism
ARISTOTLE study21
comparing apixaban 5 mg
BID vs warfarin (INR 2–3)
ongoing. AVERROES
study22,23 completed: In
warfarin-ineligible patients,
apixaban superior to ASA
(1.6% vs 3.6%; RRR of
50%; P⬍0.001) for
prevention of stroke and
systemic thromboembolism
20 500 patient ENGAGE-AF
TIMI 48 study24 is ongoing:
Compares 2 doses, Edoxaban
30 mg daily and 60 mg daily
with warfarin (INR 2–3)
RELY indicates Randomized Evaluation of Long-term anticoagulation therapY; ROCKET-AF, Rivaroxaban: Once daily, oral, direct factor Xa inhibition Compared with vitamin
K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation; ARISTOTLE, Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial
fibrillation; INR, international normalized ratio; AVERROES, Apixaban versus Acetylsalicylic Acid to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable
for Vitamin K Antagonist Treatment; ASA, acetylsalicylic acid; RRR, relative risk reduction; and ENGAGE-AF TIMI, Effective aNticoaGulation with factor xA Next GEneration in
Atrial Fibrillation.
*The US Food and Drug Administration approved 150 mg BID at a creatine clearance of ⬎30 mL/min and 75 mg BID at a creatine clearance of ⬍30 mL/min.
assigned 2).12 In patients with a CHADS2 score ⱖ2,
long-term oral anticoagulation is recommended, unless contraindicated, with a goal international normalized ratio of 2 to
3. However, patients with CHADS2 score of 1(moderate risk)
still derive benefit from long-term oral anticoagulation over
aspirin, often with lower rate of major bleeding. Therefore,
more recently, the Europeans have developed an expanded
new risk stratification score for the elderly, the CHA2DS2
vascular score, that gives a point for age over 65 years, for
being female, and for the presence of vascular disease
(peripheral arterial disease, aortic plaque, or myocardial
infarction) and 2 points for age ⬎75 years.13 This score is
cumulative and a score of ⱖ2 requires long-term oral anticoagulation. These European guidelines recognize the stroke
risk as a continuum and deemphasize the use of low-,
moderate-, and high-risk categorization.
The role of warfarin as the anticoagulant of choice is being
challenged. The most exciting advances are the direct thrombin inhibitors. Ximelagatran achieved noninferiority with
warfarin for stroke prevention, but was toxic to the liver and
not approved.14,15 In the Randomized Evaluation of Longterm anticoagulation therapY (RELY) trial,16 the direct
thrombin inhibitor dabigatran at 150 mg BID proved superior
to warfarin for stroke prevention in patients with atrial
fibrillation at risk of stroke.17 These results were achieved
with a trend toward a reduced rate of major bleeding
compared with warfarin. Dabigatran reduced intracranial
hemorrhages by 60% in the 150 mg BID dose group compared with warfarin. Gastrointestinal symptoms leading to
drug discontinuation occurred in 2.1% of patients in the 150
mg BID group compared with 0.6% in the warfarin group.
Myocardial infarction rates were low, but slightly higher in
the dabigatran group than in the warfarin group. Major
gastrointestinal hemorrhages were higher in dabigatran group
versus warfarin, 1.5% versus 1.1%. Dabigatran administration causes full anticoagulation within several hours of
ingestion. Dabigatran is effective for stroke prevention in
patients with atrial fibrillation regardless of prior warfarin
exposure.18 The US Food and Drug Administration recently
approved dabigatran for clinical use at the 150 mg BID dose
for patients whose creatinine clearance exceeded 30 mL/min
and 75 mg BID for patients between 15 and 30 mL/min.
Several novel oral anticoagulants have completed or are in
phase 3 trials (Table 3).19 –24
In our case, the patient had a history of hypertension and
diabetes mellitus, which gave him a CHADS2 score of 2 and
a CHAD2S2-VASC score of 4, with addition of 1 point for age
⬎65 years and 1 point for coronary artery disease. The patient
had no contraindication to anticoagulation and had a creatinine clearance of 70 mL/min. Dabigatran was initiated at a
dose of 150 mg BID. The patient remained in atrial fibrillation at a rate of about 70 bpm.
For rhythm control, dronedarone, amiodarone, or dofetilide
are considerations (Table 4). Flecainide and propafenone are
contraindicated because of his history of coronary artery
disease and potential for arrhythmia. Sotalol would need to be
initiated on an in-patient basis, leaving amiodarone and
dronedarone as the 2 remaining options. Dronedarone is a
newly approved hepatically metabolized antiarrhythmic agent
with a mechanism of action similar to amiodarone, but a
98
Table 4.
Circulation
July 5, 2011
Antiarrhythmic Options
Vaughn Williams
Class
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Examples
Mechanism
Indication
Potential Side Effects
IA
Procainamide disopyramide
Sodium-channel blocker. Decreases conduction
velocity and prolongs action potential duration.
Conversion of atrial flutter/fibrillation
and maintenance of sinus rhythm.
Procainamide metabolite (NAPA) can cause
prolonged QT and lupus-like syndrome and is
renally excreted. (tubular secretion). Its
excretion is inhibited by cimetidine,
trimethoprim etc. Anticholinergic effects are
common with disopyramide.
IC
Flecainide, propafenone
Sodium-channel blocker. Marked prolongation
of conduction velocity.
Used for atrial flutter/fibrillation in
the absence of structural heart
disease.
Propafenone and Flecainide are excreted by
the liver (CYP450) and has potential
interaction with several drugs (warfarin,
digoxin, etc). Flecainide caused increased
mortality after MI (CAST trial).
II
␤-Blockers (eg, propranolol, metoprolol,
atenolol)
␤ Blockade (myocardial ␤-1 receptor) and by
blocking the action of catecholamines.
Used for rate control in atrial
arrhythmias (atrial flutter/fibrillation).
Also useful to suppress ventricular
ectopy of ischemic etiology.
Generally well tolerated. Dose related slowing
of heart rate. Can cause fatigue, depression
and impotence.
III
Amiodarone, dofetilide, dronedarone,
sotalol
Prolongs action potential duration and
increases the effective refractory period.
Amiodarone and dronedarone blocks multiple
cardiac ion channels and has properties of all
Vaughn Williams drug classes.
Atrial fibrillation. All except ibutilide
are used for maintenance of sinus
rhythm. Ibutilide is used for
conversion of atrial fibrillation.
Sotalol is useful in the presence of
coronary artery disease.
Amiodarone needs close monitoring for organ
toxicity including thyroid, pulmonary, hepatic
and ocular testing. Amiodarone is a potent
inhibitor of several hepatic P 450 enzymes
and has several drug-drug interactions.
Dofetilide, Sotalol and Ibutilide can cause QT
prolongation. Sotalol and Dofetilide are
excreted by kidneys. Dronedarone is
contraindicated in decompensated heart
failure.
IV
Nondihydropyridine calcium-channel
antagonists (verapamil and diltiazem)
Interferes with calcium flux during plateau
phase of action potential.
Initial drugs of choice for
paroxysmal supraventricular
tachycardias such as AV nodal
reentrant tachycardia. Also used for
rate control in atrial arrhythmias
(atrial flutter/fibrillation).
Negative inotropy can worsen heart failure in
patients with severe left ventricular
dysfunction. Negative dromotropy can cause
bradycardia and high grade AV block.
Increase dabigatran serum levels.
V
Digoxin
Digoxin effects phase 4 activity of action
potential (potassium dependent). It decreases
conduction velocity and increases effective
refractory period.
Used for rate control in atrial
arrhythmias (atrial flutter/fibrillation).
Narrow therapeutic window. Drug interactions
are common (amiodarone, verapamil,
dronedarone increase digoxin levels).
Hypokalemia exacerbates digoxin toxicity.
Potential for high grade AV block and fatal
ventricular arrhythmias.
AV indicates atrioventricular; MI, myocardial infarction.
shorter half-life (⬇24 hours) and reduced tissue accumulation.25 History of severe heart failure is a contraindication.
Dronedarone was initiated. Dronedarone increases dabigatran
levels by 1.7 to 2-fold.
His dose of aspirin was reduced to 81 mg, and clopidogrel
was continued because of the drug-eluting stent. If the patient
had a bare metal stent placed, it would be reasonable to stop
clopidogrel at the time of warfarin or dabigatran initiation,
because there is an increased risk of bleeding with dual
antiplatelet therapy.26 –31
Ten days later, the patient remained asymptomatic. There
was more bruising noted, but no bleeding. An electric
cardioversion was planned for 3 weeks. Dronedarone was
continued. Three weeks later, the patient remained in atrial
fibrillation. He was successfully cardioverted without transesophageal echocardiography.10 Dabigatran was continued
during the procedure and for an indefinite period after
cardioversion. There were no complications. A month later,
he remained in sinus rhythm. The patient will remain on
droneadarone.
Acknowledgments
We gratefully acknowledge Dr Aaron Liu for help in editing the
manuscript.
Disclosures
Dr Ezekowitz reports receiving consulting fees, lecture fees, and
grant support from ARYx Therapeutics, Boehringer Ingelheim,
Daiichi Sankyo, and Portola, and consulting fees from AstraZeneca,
Bristol-Myers Squibb, Medtronic, Pfizer, and Sanofi-aventis. Dr
Nagarakanti received lecture fees from Boehringer Ingelheim Pharmaceuticals. Please change accordingly. The other authors report no
conflicts.
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ROCKET AF study. Am Heart J. 2010;159:340.e1–347.e1.
Lopes RD, Alexander JH, Al-Khatib SM, Ansell J, Diaz R, Easton JD,
Gersh BJ, Granger CB, Hanna M, Horowitz J, Hylek EM, McMurray JJ,
Verheugt FW, Wallentin L; ARISTOTLE Investigators. Apixaban for
Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J. 2010;159:
331–339.
Eikelboom JW, O’Donnell M, Yusuf S, Diaz R, Flaker G, Hart R, Hohnloser
S, Joyner C, Lawrence J, Pais P, Pogue J, Synhorst D, Connolly SJ. Rationale
and design of AVERROES: Apixaban versus acetylsalicylic acid to prevent
stroke in atrial fibrillation patients who have failed or are unsuitable for
vitamin K antagonist treatment. Am Heart J. 2010;159:348.e1–353.e1.
Connolly SJ , Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker
G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A,
Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van
Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A,
Dans AL, Munawar M, O’Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf
S; the AVERROES Steering Committee and Investigators. Apixaban in
patients with atrial fibrillation. N Engl J Med. 2011;364:806–817.
Ruff CT, Giugliano RP, Antman EM, Crugnale SE, Bocanegra T, Mercuri
M, Hanyok J, Patel I, Shi M, Salazar D, McCabe CH, Braunwald E. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in
patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis
In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J.
2010;160:635–641.
Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen
C, Connolly SJ; ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360:668–678.
Hansen ML, Sørensen R, Clausen MT, Fog-Petersen ML, Raunsø J,
Gadsbøll N, Gislason GH, Folke F, Andersen SS, Schramm TK, Abildstrøm
SZ, Poulsen HE, Køber L, Torp-Pedersen C. Risk of bleeding with single,
dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with
atrial fibrillation. Arch Intern Med. 2010;170:1433–1441.
Ruiz-Nodar JM, Marı́n F, Hurtado JA, Valencia J, Pinar E, Pineda J, Gimeno
JR, Sogorb F, Valdés M, Lip GY. Anticoagulant and antiplatelet therapy use
in 426 patients with atrial fibrillation undergoing percutaneous coronary
intervention and stent implantation implications for bleeding risk and
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Pascual-Figal DA, Garrido IP, Pinar E, Valdés M, Lip GY. Increased
major bleeding complications related to triple antithrombotic therapy
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Risk of major bleeding with concomitant dual antiplatelet therapy after
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Atrial Fibrillation: Outpatient Presentation and Management
Michael D. Ezekowitz, Timothy H. Aikens, Rangadham Nagarakanti and Timothy Shapiro
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Page 87
Mise au point clinique
La fibrillation auriculaire
Tableau clinique et prise en charge des patients ambulatoires
Michael D. Ezekowitz, MBChB, DPhil, FRCP ; Timothy H. Aikens, BA ;
Rangadham Nagarakanti, MD ; Timothy Shapiro, MD
as clinique—Un homme blanc de 68 ans se présente
en consultation de cardiologie pour une légère asthénie.
Le premier élément relevé est une irrégularité du pouls
nouvellement apparue. La présence d’une fibrillation
auriculaire est confirmée par l’ECG à douze dérivations. Le
patient ne présente aucun autre symptôme. Quatre mois
plus tôt, un stent à libération de médicament lui avait été
posé pour traiter une petite lésion de la portion proximale
de l’artère interventriculaire antérieure. Les antécédents
médicaux comprennent une hypertension artérielle, une
hyperlipidémie et un diabète non insulinodépendant.
La première étape consiste à déterminer si le patient est
en situation hémodynamique stable et s’il y a lieu de
l’hospitaliser pour rechercher une éventuelle pathologie
associée. Sa pression artérielle est normale (125/80 mmHg) et
il présente un rythme cardiaque irrégulier (72 battements/min)
mais bien contrôlé par la prise quotidienne de 50 mg
d’aténolol. Il n’existe aucune anomalie électrocardiographique en dehors de la fibrillation auriculaire, ce qui
est en faveur d’un processus aigu. L’auscultation objective
un court souffle systolique d’intensité 1/6 à l’apex, sans
irradiation. Il n’existe aucun signe d’insuffisance cardiaque.
L’examen neurologique est normal. Le patient prend
quotidiennement 50 mg d’aténolol, 5 mg de lisinopril, de
la metformine, 20 mg d’atorvastatine, 325 mg d’aspirine et
75 mg de clopidogrel. L’hospitalisation ne s’impose pas dans
l’immédiat.
La prise en charge va viser à éliminer une éventuelle cause
réversible de fibrillation auriculaire, à maintenir la fréquence
cardiaque de repos et d’effort dans les limites physiologiques,
à envisager la restauration du rythme sinusal et à définir les
mesures à mettre en œuvre pour prévenir la survenue d’un
accident vasculaire cérébral (AVC).
de l’examen physique et de ceux du bilan sanguin standard
(tests fonctionnels thyroïdiens, ionogramme sanguin et
dosages toxicologiques sériques et urinaires).
Les causes cardiaques de fibrillation auriculaire sont
représentées par tout processus modifiant les caractéristiques
structurales et/ou fonctionnelles du cœur. L’échocardiographie transthoracique pratiquée chez le patient révèle une
hypertrophie ventriculaire gauche modérée avec toutefois une
fonction systolique ventriculaire gauche normale, une absence
de valvulopathie cardiaque, une oreillette gauche normale et
une absence d’épanchement péricardique. L’éventualité d’un
événement ischémique aigu apparaît improbable compte tenu
de l’absence de signe électrocardiographique d’ischémie,
de trouble segmentaire de la mobilité pariétale à l’échocardiographie et de symptômes ischémiques.
C
Régularisation de la fréquence cardiaque
Le rétablissement d’un rythme cardiaque normal, au repos
comme à l’effort, est l’élément clé de la prise en charge des
patients atteints de fibrillation auriculaire. Dans le cas qui
nous occupe, le patient recevait un bêtabloquant pour traiter
sa maladie coronaire et son hypertension artérielle. Sa
fréquence cardiaque à l’admission était acceptable. Actuellement, les avis sont partagés quant à la question de savoir s’il y
a lieu de privilégier la régularisation stricte de la fréquence
cardiaque de repos et d’effort par rapport à une attitude plus
souple. Selon une récente étude, cette dernière approche serait
acceptable.1 Les médicaments pouvant être utilisés en vue de
maintenir la fréquence cardiaque d’un patient dans les limites
physiologiques comprennent les bêtabloquants, les inhibiteurs
calciques tels que le diltiazem et le vérapamil ainsi que la
digoxine. Les bêtabloquants sont particulièrement utiles
lorsque la fibrillation auriculaire est associée à une maladie
coronaire ou à une ischémie myocardique. Les inhibiteurs
calciques sont efficaces pour régulariser le rythme cardiaque à
court et long termes, mais doivent être évités chez les patients
atteints d’insuffisance cardiaque systolique en raison de leur
effet inotrope négatif. La digoxine peut être intéressante en
association avec un bêtabloquant chez les patients insuffisants
cardiaques. Dans le cas présent, un bêtabloquant est recommandé compte tenu de la coexistence d’une maladie coronaire
et d’une hypertension artérielle.
Causes réversibles de fibrillation auriculaire
Pour la commodité, les causes réversibles de fibrillation
auriculaire sont séparées en causes cardiaques et extracardiaques. Chez ce patient, ces dernières (déséquilibre
électrolytique, hyperthyroïdie, fièvre liée à une quelconque
origine [notamment une pneumopathie], prise de médicaments ou de drogues à usage récréatif et consommation
d’alcool) sont écartées au vu des antécédents, des résultats
Institut Lankenau de Recherche Médicale, Wynnewood, Pennsylvanie, Etats-Unis (M.D.E., T.H.A., T.S.) ; et Faculté de Médecine de l’Université d’Etat
de la Louisiane, Nouvelle-Orléans, Louisiane, Etats-Unis (R.N.).
Correspondance : Michael D. Ezekowitz, MBChB, DPhil, FRCP, Lankenau Institute for Medical Research, 100 Lancaster Ave, Suite G36, Wynnewood,
PA 19096. E-mail: [email protected]
(Traduit de l’anglais : Atrial Fibrillation. Outpatient Presentation and Management. Circulation. 2011;124:95–99.)
© 2012 American Heart Association, Inc.
Circulation est disponible sur http://circ.ahajournals.org
87
08:38:12:04:12
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Circulation
Tableau 1.
Mars 2012
Etudes ayant comparé le ralentissement de la fréquence cardiaque versus la restauration du rythme sinusal
Cardioversion
Les essais randomisés menés pour comparer le ralentissement
de la fréquence cardiaque à la cardioversion n’ont objectivé
aucune supériorité de l’une ou l’autre de ces stratégies de
prise en charge en termes d’amélioration de la mortalité
(Tableau 1).2–7 Il semble néanmoins que le rétablissement
précoce du rythme sinusal contribue à réduire fortement
le remodelage de l’oreillette gauche, tant mécanique
qu’électrique.8 Les autres indications de la cardioversion sont
déterminées par la présence de symptômes chez le patient.
Habituellement, le maintien à long terme du succès de la
cardioversion réclame la prescription concomitante d’un
antiarythmique.9 Lorsqu’un patient présente une récidive de
fibrillation auriculaire symptomatique que l’on a tenté sans
succès de réduire par l’administration d’un antiarythmique,
il y a lieu d’envisager un traitement ablatif par cathéter. La
technique la plus fréquemment employée à l’heure actuelle
consiste à supprimer les zones gâchettes en isolant les veines
pulmonaires de l’oreillette gauche par la réalisation de lésions
linéaires ou circulaires. Dans le cas qui nous occupe, le patient
présente un état hémodynamique stable, de sorte que la
mise en œuvre d’une cardioversion par choc électrique
externe est différée (dans l’éventualité où le rythme sinusal se
rétablirait spontanément) sans pour autant être définitivement exclue. La recommandation actuelle est d’instaurer une
08:38:12:04:12
Page 88
anticoagulation thérapeutique au moins 3 semaines avant la
cardioversion et de la poursuivre pendant un minimum de 4
semaines une fois celle-ci pratiquée. La sous-analyse sur les
cardioversions effectuée dans le cadre de l’étude RE-LY a
montré qu’il est raisonnablement envisageable de remplacer la
warfarine par le dabigatran pour prévenir le risque d’AVC
chez les patients relevant d’une cardioversion.10
Prévention des accidents vasculaires cérébraux
La principale complication de la fibrillation auriculaire est
l’AVC. L’approche pharmacologique essentielle pour prévenir
la survenue d’un tel événement est l’anticoagulation. La
décision d’instaurer un traitement anticoagulant implique
toutefois de mettre en balance la prévention de l’AVC et
le risque hémorragique. Des algorithmes de stratification du
risque sont disponibles à cette fin (Tableau 2). Le premier
d’entre eux a été élaboré en 1995 par le groupe des Atrial
Fibrillation Investigators.11 Ces derniers ont conçu un système
de cotation du risque toujours utilisé, qu’ils ont désigné par
l’acronyme CHADS2 (l’insuffisance cardiaque congestive [C],
l’hypertension artérielle [H], l’âge égal ou supérieur à 75 ans
[A] et le diabète [D] comptent chacun pour 1 point ; les
antécédents d’AVC ou d’accident ischémique transitoire
[AIT] comptent pour 2 points [S2]).12 Chez les patients dont
le score CHADS2 est égal ou supérieur à 2, un traitement
Page 89
Ezekowitz et al
Tableau 2. Modèles de stratification du risque d’accident
vasculaire cérébral lié à la présence d’une fibrillation
auriculaire
anticoagulant oral au long cours est recommandé s’il n’existe
pas de contre-indication, en veillant à maintenir le rapport
normalisé international entre 2 et 3. Cela étant, même lorsque
le score CHADS2 est de 1 (traduisant un risque modéré),
un traitement anticoagulant oral à long terme demeure
préférable à l’administration d’aspirine, l’incidence des
épisodes hémorragiques graves étant souvent plus faible. Plus
récemment, les Européens ont élaboré un score de risque plus
étoffé spécifiquement destiné au sujet âgé, le score vasculaire
CHA2DS2, dans lequel l’âge supérieur à 65 ans, le sexe féminin
et la présence d’une affection vasculaire (artériopathie
périphérique, plaque aortique ou infarctus du myocarde)
sont cotés 1 point chacun, alors que l’âge supérieur à 75 ans
compte pour 2 points.13 Ce système de cotation est cumulatif,
un score de 2 ou plus justifiant l’instauration d’un traitement
anticoagulant oral à long terme. Ces recommandations
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Prise en charge de la FA
89
européennes avalisent la notion selon laquelle le risque d’AVC
réalise un continuum, minimisant par là même l’importance
jusqu’alors accordée à la classification en risques faible,
modéré et élevé.
La place privilégiée accordée à la warfarine dans le traitement anticoagulant est aujourd’hui remise en question. Les
progrès les plus marquants ont été accomplis dans le domaine
des inhibiteurs directs de la thrombine. Le ximélagatran a fait
la preuve de sa non-infériorité par rapport à la warfarine dans
la prévention des AVC, mais n’a pas reçu d’autorisation
de mise sur le marché en raison de son hépatotoxicité.14,15
Dans l’essai RE-LY (Randomized Evaluation of Long-term
anticoagulation therapY [évaluation randomisée du traitement anticoagulant au long cours]),16 l’administration de
dabigatran, un autre inhibiteur direct de la thrombine, à la
posologie de 150 mg deux fois par jour s’est avérée supérieure
au traitement par la warfarine pour prévenir la survenue
d’AVC chez les patients exposés à ce risque du fait
de l’existence d’une fibrillation auriculaire.17 Il a également
été noté une tendance à la diminution de l’incidence
des hémorragies graves comparativement à celle relevée
sous warfarine. Dans le groupe traité par deux prises
journalières de 150 mg de dabigatran, le taux d’hémorragies
intracrâniennes a été abaissé de 60 % comparativement à
celui enregistré sous warfarine. Toutefois, l’incidence des
symptômes digestifs ayant conduit à interrompre le traitement
a été de 2,1 % dans le groupe traité par le dabigatran à raison
de 150 mg deux fois par jour, contre seulement 0,6 % dans
le groupe ayant reçu de la warfarine. Les taux d’infarctus
du myocarde ont été faibles dans les deux groupes, mais
l’incidence de cet événement a été légèrement plus élevée sous
dabigatran que sous warfarine. Les hémorragies digestives
graves ont été plus fréquentes dans le groupe traité par le
dabigatran que dans celui ayant reçu de la warfarine (1,5 %
contre 1,1 %). L’administration de dabigatran induit une
anticoagulation complète dans les heures qui suivent la prise.
Le médicament est efficace pour prévenir le risque d’AVC chez
les patients en fibrillation auriculaire, que ces derniers aient
été ou non précédemment exposés à la warfarine.18 La Food
and Drug Administration des Etats-Unis a récemment
autorisé l’utilisation clinique du dabigatran à la posologie de
150 mg deux fois par jour chez les patients dont la clairance
de la créatinine excède 30 ml/min et à raison de 75 mg deux
fois par jour chez ceux ayant une clairance de la créatinine
comprise entre 15 et 30 ml/min. Plusieurs nouveaux anticoagulants oraux ont d’ores et déjà achevé leur cycle
d’évaluation ou sont en cours d’expérimentation dans des
essais de phase III (Tableau 3).19–24
Le patient dont il est ici question est hypertendu et
diabétique, ce qui lui a fait attribuer un score CHADS2 de 2 et
un score CHAD2S2 vasculaire de 4 puisque son âge supérieur
à 65 ans et sa maladie coronaire comptent chacun pour un
point supplémentaire. Le patient ne présente aucune contreindication à l’administration d’un traitement anticoagulant et
sa clairance de la créatinine est de 70 ml/min. Il lui est donc
prescrit du dabigatran à la posologie de 150 mg deux fois par
jour. Le patient demeure en fibrillation auriculaire, avec une
fréquence cardiaque d’environ 70 battements/min.
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Circulation
Tableau 3.
Mars 2012
Nouveaux anticoagulants oraux
Pour restaurer le rythme sinusal, il est envisageable d’utiliser
la dronédarone, l’amiodarone, ou le dofétilide (Tableau 4).
Le flécaïnide et la propafénone sont contre-indiqués chez
ce patient en raison de ses antécédents coronariens et du
potentiel arythmogène de ces médicaments. Le sotalol ne peut
être instauré que dans le cadre d’une hospitalisation, de sorte
que l’amiodarone et la dronédarone demeurent les deux seules
options possibles. La dronédarone est un antiarythmique
nouvellement apparu sur le marché, qui est métabolisé
par le foie et répond au même mécanisme d’action que l’amiodarone, mais se distingue de celle-ci par sa demi-vie plus
courte (de l’ordre de 24 heures) et par son accumulation
tissulaire plus faible.25 Le médicament est contre-indiqué en
cas de préexistence d’une insuffisance cardiaque sévère. Le
patient est finalement placé sous dronédarone. Celle-ci a
toutefois pour effet d’élever le taux sérique de dabigatran à un
niveau 1,7 à 2 fois supérieur.
La dose d’aspirine prescrite au patient est abaissée à 81 mg,
le clopidogrel étant par ailleurs poursuivi en raison de la
présence du stent à libération de médicament. Si le stent
posé avait été en métal nu, il eût été raisonnable d’arrêter le
clopidogrel à l’instauration de la warfarine ou du dabigatran,
car la bithérapie antiagrégante plaquettaire augmente le
risque hémorragique.26–31
08:38:12:04:12
Page 90
Dix jours plus tard, le patient est toujours asymptomatique.
Il présente davantage d’hématomes, mais aucun épisode
hémorragique n’a été constaté. Une cardioversion par choc
électrique externe est programmée à trois semaines. La
dronédarone est poursuivie. Trois semaines plus tard, le
patient demeure en fibrillation auriculaire. La cardioversion
est entreprise avec succès, sans pratiquer d’échocardiographie
transœsophagienne.10 Le dabigatran est maintenu pendant
l’intervention et poursuivi pendant une durée indéfinie après
cette dernière. Aucune complication n’est enregistrée. Un
mois plus tard, le patient est toujours en rythme sinusal.
Il sera maintenu sous dronédarone.
Remerciements
Nous remercions chaleureusement le Dr Aaron Liu pour l’aide
apportée à la rédaction du présent manuscrit.
Déclarations
Le Dr Ezekowitz a été rémunéré en qualité de consultant et de conférencier par ARYx Therapeutics, Boehringer Ingelheim, Daiichi
Sankyo et Portola, ces sociétés ayant, en outre, subventionné ses
travaux ; il a également été rémunéré en qualité de consultant par
AstraZeneca, Bristol-Myers Squibb, Medtronic, Pfizer et SanofiAventis. Le Dr Nagarakanti a été rémunéré en qualité de conférencier
par Boehringer Ingelheim Pharmaceuticals. Veuillez modifier comme
il convient. Les autres auteurs n’ont aucun conflit d’intérêts à signaler.
Page 91
Ezekowitz et al
Tableau 4.
91
Options en matière d’antiarythmiques
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